The control of drug-related toxicity (e.g. myelosuppression, diarrhea, mucosal toxicity, and infection) has been a major concern throughout the history of cancer chemotherapy. Substances conventionally used in cancer chemotherapy are e.g. antifolates, anthracyclines, and antineoplastic agents.
Antifolates, or folate antagonists, constitute a class of antimetabolites, and are active chemotherapeutic agents for many solid tumor and hematologic malignancies (Thomas Purcell W et al; “Novel Antifolate Drugs”, Evolving Therapies, pp 114-125, March 2003).
For many years, methotrexate (MTX) has been the major antifolate antimetabolic agent used in clinical medicine. The primary cellular target of MTX is the enzyme dihydrofolate reductase (DHFR) and thus, MTX is a single enzyme targeting antifolate. There are also other approved agents which only attack single enzyme targets, e.g. 5-fluorouracil (5-FU), which inhibit thymidylate synthase (TS) (Scagliotti, Giorgio V et al; Phase II Study of Pemetrexed With and Without Folic Acid and Vitamin B12 as Front-Line Therapy in Malignant Pleural Mesothelioma”, Journal of Clinical Oncology, Vol 21, No 8, Apr. 15, 2003, pp 1556-1561).
Although response to treatment is observed in patients, many of them relapse due to development of resistance. Drug resistance is often a limiting factor in successful chemotherapy with single enzyme targeting antifolates (Banerjee D et al; “Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase”, Biochimica et Biophysica Acta 1587 (2002) 164-173).
Novel antifolates have been developed to improve the efficacy and toxicity profile or to decrease the various known mechanisms of resistance to antifolate therapy.
These novel antifolates are multi-targeting antifolates that have demonstrated broad-spectrum antitumor activity. This new generation of antifolates inhibits several key folate-requiring enzymes of the thymidine and purine biosynthetic pathways, in particular thymidylate synthase, DHFR and GARFT (glycinamide ribonucleotide formyltransferase), by competing with reduced folates for binding sites. The consequent inhibition of intracellular folate metabolism leads to the inhibition of cell growth (Niyikiza Clet et al; “Homocysteine and Methylmalonic Acid: Markers to Predict and Avoid Toxicity from Pemetrexed Therapy”, Molecular Cancer Therapeutics, Vol 1, 545-552, May 2002).
The cytotoxic activity and subsequent effectiveness of antifolates can be associated with substantial toxicity for some patients. Antifolates, as a class, have been associated with sporadic severe myelosuppression with gastrointestinal toxicity. A combination of such toxicities can carry a high risk of mortality. The inability to control these toxicities has led to the discontinuation of clinical development of some antifolates, and complicated the clinical development of others (Niyikiza Clet et al; “Homocysteine and Methylmalonic Acid Markers to Predict and Avoid Toxicity from Pemetrexed Therapy”, Molecular Cancer Therapeutics, Vol 1, 545-552, May 2002).
U.S. Pat. No. 5,376,658 (Spears et al) discloses the use of CF2FH4, and its solution product isomer FH4, as a modulator of 5-FU in cancer chemotherapy. Also disclosed is a method of using CF2FH4 or FH4 in order to reduce the toxicity of an anti-folate drug which has been administered to a patient. The anti-folate drugs disclosed are methotrexate, trimetrexate, nitrous oxide, and dideoxytetrahydrofolic acid, all of which belong to the group of single enzyme targeting antifolates.
Treatment with specific TS inhibitors like 5-FU in combination with folinic acid has been shown to reduce side-effects without reducing tumor effect. It seems that folate deficiency may have contributed to the toxicity in some cancer patients, and nutritional supplementation with folic or folinic acid had led to a reduction in toxicity and treatment-related deaths with preservation of anticancer activity (Calvert H; “Folate status and the safety profile of antifolates”; Semin Oncol 2002; 29:3-7).
In a recent study, Niyikiza et al reported that supplementation with folic acid may lead to a better safety profile in patients treated with pemetrexed, and possibly to an improved efficacy. Toxicity could be modulated by folic acid supplementation, and the maximum tolerated dose could be increased (Niyikiza C et al, “Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy”; Mol Cancer Ther 2002; 1:545-52).
However, the metabolism of folic acid is a very complex process, and many metabolic steps are required in order to achieve the active substances of the folic acid metabolism. Folic acid is the most oxidized and stable form of folate and must be deconjugated, reduced, and methylated to be metabolically active in the cell (Kelly G S, “Folates: supplemental forms and therapeutic applications”; Altern Med Rev 1998; 3:208-20).
Folic acid supplementation to reduce toxicity is thus actually quite inefficient, and may additionally lead to unwanted metabolic intermediates. Until now, no satisfactory way of reducing the toxicity of multi-targeting antifolates has been proposed. Considering the very promising action of antifolates, a possibility to efficiently reduce their side effects is very much sought-after. There is thus a need for a way of reducing toxicity, and at the same time maintaining or improving the efficiency of multi-targeting antifolates, in order to be able to use them efficiently in clinic.